This invention concerns a cement for surgical purposes, a method for producing brushite as temporary bone replacement material, and a temporary bone replacement material.
A number of such hydraulic cements based on calcium phosphates for use in surgery are known in the prior art; they are prepared from two components (powder/liquid) by mixing them intra-operatively and applying them in pasteous consistency to the appropriate site where they harden in situ. The disadvantages of the prior art hydraulic cements based calcium phosphates are:
a. impracticable short setting times which do not allow their use for elaborate surgical procedures;
b. poor injectability, i.e. the fresh cement paste tends to clog the injection needle, and/or disintegrates in contact with physiological liquids, which prevents its implantation by minimal invasive surgery procedures;
c. low compacity, i.e. current hydraulic cements need larger amounts of mixing water in order to have them injectable or to confer them a convenient setting time, which results in very low ultimate mechanical strength after hardening.
In U.S. Pat. No. 4,880,610, a method is disclosed for making an in situ calcium phosphate mineral composition by combining water-free phosphoric acid crystals with a calcium source, which leads to a hydroxyapatite. It is clear that the use of 100% phosphoric acid in the operating room and the application of a paste containing 100% phosphoric acid in the human body must be considered a not ideal procedure that requires improvement. Furthermore the hydroxyapatite material produced by this known method will have a long resorption period, which is not commensurate to the rate of the bone remodelling. The disadvantage of prolonged resorption is that the bone treated by cement will remain for a prolonged time in abnormal biomechanical situation, which may develop secondary post-operational problems. Furthermore the unresorbed cement may still break down in pieces or fragments after prolonged mechanical loading, which increases the probability of post-operational complications, e.g. aseptic inflammatory reactions. The resorption rate of the ideal cement should match as closely as possible the spontaneous rate of new bone formation, which is around 20 micrometers per day.
From GB-2 260 977 a calcium phosphate composition is known using alpha-TCP particles. Alpha-TCP particles are much more reactive than beta-TCP particles and therefore lead to a setting time, when admixed to monocalcium phosphate monohydrate and water, that is much too fast (a few seconds), and hence difficult to control.
From an article of MIRCHI A A ET AL. appeared in Biomaterial 1989, Vol. 10, No. 9, Nov. 1, 1989, pages 634-638, a calcium phosphate cement is known with commercially available MCPM and xcex2-TCP particles the Ca/P ratio of which is 1.50. The disadvantages of xcex2-TCP particles with a Ca/P ratio of 1.50 is their relatively high reactivity which makes them inappropriate for a surgical cement.
The present invention is directed toward solving the above-described problems. The present invention provides a cement for surgical purposes, a method for producing a temporary bone replacement material, and a temporary bone replacement material.
The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming part of this disclosure. For the better understanding of the invention, its operating advantages and specific objects attained by its use, reference should be done to the accompanying examples in which preferred embodiments of the invention are illustrated in detail.
The first component of the cement according to the invention comprises beta tertiary calciumphosphate xcex2-Ca3(PO4)2(xcex2-TCP) particles in an amount preferably greater than about 50% by weight and one of the following substances:
monocalcium phosphate Ca(H2PO4)2(MCPA) particles; or
monocalcium phosphate monohydrate Ca(H2PO4)2.H2O (MCPM) particles; or
phosphoric acid.
Alternative a) and b) are the preferred ones; the phosphoric acid may be used either in solid or in liquid form.
The Ca/P atomic ratio of the xcex2-TCP particles of the first component is preferably comprised between 1.35 to 1.499. Purposefully it is comprised between 1.45 to 1.47 and typically between 1.455 to 1.465. The advantage of the Ca/P atomic ratio used in the invention is the lower reactivity of the xcex2-TCP particles. A lower Ca/P atomic ratioxe2x80x94below 1.5xe2x80x94can be achieved in avarious ways. One possiblity is the calcination and sintering of DCP [CaHPO4]/hydroxyapatite [Ca5(PO4)3OH]) mixtures. The Ca/P ratio is then controlled by the proportion of the two components. To obtain a Ca/P ratio of exactly 1.50 one should mix 10 g of DCP with 36.91 g HA. To obtain a Ca/P ratio of 1.35 one has to mix 10 g DCP with 13.6 g of HA. Alternatively DCP could be replaced by DCPD (CaHPO4.H2O), MCPM [Ca(H2PO4)2.H2O], CaPP (Ca2P2O7) or OCP. The beta-TCP particles with a Ca/P ration inferior to 1.50 can also be obtained by adding small amounts of DCP, DCPD, MCPM or OCP to a pure beta-TCP powder, and then mix and sinter the mixture to homogenize it.
Another way is to add minor amounts of Na4P2O710.H2O (NaPPH) to the xcex2-TCP particles which retard their dissolution in a synergetic way. Consequently the setting time of the hydraulic cement is significantly increased. The presence of minor amounts of CaPPH increases also the sintering ability of the xcex2-TCP particles, hence enabling the production of dense xcex2-TCP particles. Non-dense xcex2-TCP particles absorb the mixing liquid during setting. As a following, more mixing liquid must be used to knead the cement, provoking a decrease of the mechanical properties of the cement after hardening. If the amount of CaPPH is too large (Ca/P ratio below 1.35) the mechanical properties of the cement decrease drastically.
The mean specific surface area of the xcex2-TCP particles must be less than 10 m2/g otherwise the cement has poor mechanical propertiesxe2x80x94due to a large porosity resulting from the large volume of mixing liquidxe2x80x94and a setting time which is too short for practical purposes. Preferably, the xcex2-TCP particles have a mean specific surface area of 0.0137 to 2.000 m2/g. More preferably, the xcex2-TCP particles have a mean specific surface area of 0.8 to 1.5 m2/g.
Setting time of the cement according to the invention as measured at 25xc2x0 C. should be at least 2 minutes, typically at least 3 minutes and preferably at least 5 minutes.
According to a preferred embodiment of the invention the first component is divided into two subcomponents A and B, subcomponent A comprising the MCPA and/or MCPM particles and subcomponent B comprising the xcex2-TCP particles and the setting rate controller.
The second component comprises water and may further comprise orthophosphoric acid (OPA) and/or sulphuric acid (SA), which again take the function of a setting rate controller and also lead to an improved microstructure of the final brushite (DCPD) crystals.
The third component comprises a calcium phosphate with a Ca/P ratio different from 1.5. The Ca/P ratio is preferably less than 1.5, more than 1.5, or more preferably in the range of 1.35 to 1.49. The third component comprises from 1-99 volume % of the hardened mass. The third component comprises particles having an average diameter which is larger than the average diameter of said beta tertiary calciumphophate xcex2-Ca3(PO4)2(xcex2-TCP) particles of said first component.
After mixing the three components a hardened mass is formed comprising brushite CaHPO4.2H2O (DCPD), which based on its solubility is used to accelerate the resorption rate compared to HA.
The total weight WTCP of the xcex2-TCP particles of the first and third components should preferably be larger than the stoichiometric weight
WT=WMCPA/0.7546+WMCPM/0.8127+WOPA/03159+WSA/0.3162 where WMCPA, WMCPM, WOPA and WSA are, respectively, the weights of MCPA, MCPM, OPA and SA used.
Further the weight WTCP should be in the range of 1.2 WTxe2x89xa6WTCPxe2x89xa610.0 WT, and more preferably in the range of 2 WTxe2x89xa6WTCPxe2x89xa65 WT. 
The first component may further comprise a setting rate controller chosen from the group of sodium pyrophosphate, potassium pyrophosphate, sodium acetate, potassium acetate, sodium citrate, potassium citrate, sodium phosphocitrate, potassium phosphocitrate, sodium sulphate or potassium sulphate, calcium sulphate hemihydrate CaSO4.0.5H2O (CSH), sodium pyrophosphate Na4P2O7.10H2O (NaPPH), sodium dihydrogen pyrophosphate Na2H2P2O7(NaHPP), calcium pyrophosphate Ca4P2O7(CaPP), magnesium sulphate and sodium or potassium biphosphonate.
In a further preferred embodiment of the invention a third component consisting of particles having an average diameter which is larger than the average diameter of said beta tertiary calciumphosphate xcex2-Ca3(PO4)2(xcex2-TCP) particles of said first component is added. This leads to conglomerate structure of the finally set cement, whereby the third component particles are embedded in the brushite matrix formed by the setting process. The average particle diameter of said third component should be at least two times larger, preferably at least 10 times larger compared to the average diameter of the beta tertiary calciumphosphate xcex2-Ca3(PO4)2(xcex2-TCP) particles of the first component. Preferably the average particle diameter of said third component should be in the range of 50 to 2000 xcexcm. The particles of the third component may consist of hydroxyapatite particles or of polymeric particles, e.g. lactides, polysaccharides, collagenes or proteins.
In a further preferred embodiment of the invention two different types of xcex2-TCP particles are used, the first type being particles having a median particle size of 5 xcexcm with less than 10 volume % of the particles being smaller than 1 xcexcm; and the second type being particles having an average diameter in the range of 150 to 500 xcexcm, preferably in the range of 250 to 400 xcexcm. The average particle diameter of said third component should be in the range of 50 to 2000 xcexcm, preferably between 250 and 750 xcexcm.
The volume VL of the second component should preferably be equal or superior than the volume VT=(WMCPAxc3x970.615+WMCPMxc3x970.5+WOPAxc3x971.102+WSA1.101) ml/g of the first component. The volume VL is typically in the range of 0.5 VTxe2x89xa6VLxe2x89xa610.0 VT, preferably in the range of 1.2VTxe2x89xa6VLxe2x89xa62.0 VT.
One of the two components may further comprise a biodegradable polymer for controlling the consistency of the cement paste resulting from mixing of the two components, and its cohesion in physiological liquids. The biodegradable polymer may be selected from the group of polysaccharide derivatives, preferably hyaluronic acid, dextran, hydroxypropyl-methyl cellulose; chitin derivatives, preferably chitosan; xanthan gum; agarose; polyethyleneglycols (PEG), polyhydroxyethylenemethacrylats (HEMA), synthetic and natural proteins or collagens.
The first component may further comprise pharmaceutically or physiologically active substances, preferably selected from the group of antibiotics, anti-inflammatory, anti-cancer drugs and bone growth factors. The antibiotics is preferably a gentamycin or a gentamycin salt, typically gentamycin sulphate. Other gentamycin salts can be used provided their solubility is in the range of 100 to 2500 mg/l. The antibiotics is selected from the group of aminoglycosides, vancomycins, gentamycins or salts thereof, preferably gentamycin sulphate or gentamycin crobefat. The antibiotics can comprise a mixture of aminoglycosides, such as a mixture of vancomycin with gentamycin, which is preferred.
The cements according to the invention may be used as bone substitute in dental and maxillofacial surgery (alveolar ridge reconstruction, dental socket filling), for orthopaedic applications (bone fracture repair, bone augmentation) and for local drug delivery (antibiotics, anti-inflammatory and anti-cancer drugs).
In a preferred embodiment the particles of the third component are made from another material than beta tertiary calciumphosphate xcex2-Ca3(PO4)2(xcex2-TCP). The particles of said third component are preferably made from a material selected from the group of: hydroxyapatite; biphasic calcium phosphonate (BCP) (HA/xcex2-TCP) mixtures; bioglasses; or polymeric materials. The advantage is the differential degradation of such a cement. The matrix of the cement is degraded faster than the residual granulates. This is particularly useful for the application in the osteoporose field or for the ridge reconstruction of the jaw, where a slower degrading granulate, e.g. made from hydroxyapatite or BCP is desired.
Five specific examples are reported below for producing the temporary bone replacement materials according to the invention.